Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, fluvastatin, cervastatin and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of these inhibitors are produced by fermentation using microorganisms of species belonging to the Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus. Some inhibitors are the fermentation products themselves, or are obtained by treating the fermentation products using chemical methods.
The present invention relates to amorphous form HMG-CoA reductase inhibitors, useful as a pharmaceutical substance, and to a method for production and isolation thereof. HMG-CoA reductase inhibitors, are used for the treatment of hyperlipidemia and hypercholesterolemia, risk factors for arteriosclerosis and coronary heart disease.
U.S. Pat. No. 5,273,995, describes that the R-form of the ring opened acid of the atorvastatin lactone form inhibits the biosynthesis of cholesterol. Atorvastatin in its calcium salt form, i.e. amorphous [R—(R*, R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (2:1), is discussed in the literature.
U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,248,793; 5,280,126; 5,342,952, which are herein incorporated by reference, describe various processes and key intermediates for preparing atorvastatin calcium.
However, the processes mentioned in the above patents do not produce atorvastatin calcium in its amorphous form consistently. Often a mixture of crystalline and amorphous form is obtained which is not suitable for filtration and drying and therefore they are not a desirable processes for large-scale production.
PCT application WO 97/03959, discloses novel crystalline forms of atorvastatin calcium designated as Form I, Form II, and Form IV and a method for their preparation. PCT application WO 97/03960 describes a procedure for converting the crystalline form of atorvastatin to the amorphous form.
The process described in the later mentioned PCT application involves dissolving the crystalline atorvastatin (Form-I) in a non hydroxylic solvent like tetrahydrofuran or mixtures of tetrahydrofuran and toluene, followed by removal of the solvents under high temperature (about 90° C.) and high vacuum (about 5 mm). This process may not be suitable on a large scale as the conditions used for drying may lead to degradation of the product.
PCT application WO 00/71116 claims a process for the preparation of amorphous atorvastatin calcium where the crystalline form is dissolved in a non-hydroxilic solvent, treated with a non-polar hydrocarbon anti-solvent, and results in the amorphous form when the solvent in removed.
Pravastatin was first reported as a metabolite of compactin in U.S. Pat. No. 346,227. PCT Application WO01/43723 describes certain novel forms of pravastatin which are characterized by X-Ray patterns.